Certain derivatives of the 1-deaza-7,8-dihydropteridine ring system are about as cytotoxic as methotrexate in cell culture and have shown significant activity against experimental tumors (L1210, P338) in mice, including the methotrexate-resistant cell line of lymphocytic leukemia P388. The mode of action of these compounds is unknown but appears to be different from that of the conventionally used anticancer agents. The 1-deazadihydropteridines are potentially useful in the treatment of tumors resistant to the known agents and in precluding the occurrence of resistance when combined with other agents. Our collaborative research program will be directed toward the synthesis of congeners of the active 1-deaza-7,8-dihydropteridines, the identification of the structural features necessary for activity, th determination of the site(s) of action by biochemical studies, and the evaluation of in vitro and in vivo biological activity against both sensitive and resistant antineoplastic systems. Studies on the metabolism of these agents, the identification of the sites of action, and biological activity observed in the primary screen (P388) will provide guidance for the synthesis of additional structures. In addition, new structures will be synthesized to optimize lipophilic-hydrophilic balance if this physical parameter and activity appear to be related.